ANTI-PARKINSON DISEASE Flashcards
Young onset parkinson’s disease
21-40y/o
Juvenile onset parkinson’s disease
=< 20y/o
- higher frequency of genetically inherited PD
Pathophysiology of PD
- Impaired clearing of abnormal/damaged proteins by ubiquitin-proteasomal system
- Accumulations of toxic proteins, aka aggresomes or lewy bodies, leading to apoptosis of dopaminergic neurons in substantia nigra
What does lewy bodies contains?
alpha-synuclein & ubiquitin
lewy body eosinophilic cytoplasmic inclusions
Why is the degeneration of dopaminergic neurons in substantia nigra important?
- Substantia nigra has dopaminergic projections into the basal ganglia
- Basal ganglia is important to facilitate and modulate movements initiate by motor cortex
Diagnosis of PD
No reliable diagnostic marker for PD Hence, 1. Presence of clinical features 2. Elimination of alternative diagnosis eg atypical parkinsonian disorders 3. Neuroimaging of dopaminergic neurons in substantia nigral
Parkinson’s disease = Parkinsonian syndrome?
No
3 cardinal features of PD
- Rest tremors
- Rigidity
- Bradykinesia
Non-motor manifestation of PD (4)
- Autonomic (postural hypotension & instability)
- Neuropsychiatric
- Olfactory
- Sensory
- relatively resistant and may be worsened by dopaminergic agents (eg Levodopa, MAO-B, Dopaminergic agonist)
- more prominent in later stages of disease
- significant disability
- common in PD
Progression of disease
- progressive disease
- rate of disability progression is most marked in early years of the disease, before plateauing
- significant disability 10-15 years after onset
- patients become increasingly dependent in their daily activities
- motor fluctuations, dyskinesia & non-motor symptoms are more common at later stages
How to decide what medications to use? (6)
Individualised
- age
- stage of disease
- level of activity
- psychological conditions
- associated medical conditions
- patient factors (eg occupation)
Start low, go slow
Early symptomatic disease without complications
- may not even need to start medications if coping well
- emphasize non-pharmacological (4) :
- stretching & maintaining balance and posture
- healthy and balanced diet
- knowledge on disease
- social support
HOWEVER, rate of disability progression most marked in early years of the disease
Classes of anti-PD drugs (6)
- Levodopa +/- peripheral decarboxylase inhibitor (benserazide/carbidopa)
- Anticholinergics (trihexyphenidyl - Artane)
- MAO-B inhibitors (selegiline - Jumex)
- COMT (Entacapone & Tolcapone)
- Dopamine agonist (Bromocriptine, Pergolide, Pramipexole, Piribedil, Ropinirole)
- Amantadine
Treatment for mild PD
MAO-B inhibitors (selegine - Jumex)
Treatment for young patients with PD
Dopamine agonists > Levodopa
Levodopa MOA
- dopamine precursor
- 2-in-1 preparation with peripheral decarboxylase to increase levodopa uptake by brain
benserazide or carbidopa
ADR of Levodopa
Short term :
- n/v
- postural hypotension
Long term :
- motor fluctuations
- irreversible tardive dyskinesia (10%/year)
Hence, even though it is gold standard, the dose of levodopa must be kept to minimum.
Why must the dose of Levodopa be kept to minimum? How?
This is because Levodopa can cause irreversible tardive dyskinesia (10%/year)
Dose of Levodopa can be kept minimum by adopting adjunct therapy with :
1. Anti-cholinergics
2. COMT
3. Dopamine agonists
Anti-cholinergics MOA
- symptomatic treatment to control tremors
- peripherally acting agents can use for sialorrhoea (excessive salivation)
ADR of anti-cholinergics
- dry mouth
- sedation, blurred vision
- constipation
- urinary retention
- insomnia, confusion, hallucinations, delirium
esp in elderly
Example of anti-cholinergics
Trihexyphenidyl (Artane)
- 2-15mg/day
Anticholinergics for PD
- Symptomatic monotherapy
2. Adjunctive therapy to Levodopa
MAO-B inhibitors MOA
- inhibit MAO-B from breaking down dopamine
- increase synaptic dopamine
- may delay the dopaminergic nigral brain cell degeneration
ADR of MAO-B inhibitors (7)
HAPICNV
- heartburns
- anxiety
- palpitation
- insomnia
- confusion
- nightmares
- visual hallucinations
- loss of appetite
- n/v
- constipation
- dizziness
- headache
Example of MAO-B inhibitor
Selegiline (Jumex)
MAO-B inhibitors for PD
Symptomatic monotherapy in early PD for mild parkinsonian activity
COMT MOA
- Catechol-O-methyltransferase inhibitors
- blocks enzyme that converts Levodopa to inactive form, hence extend the duration of action of Levodopa
- increase levodopa available to enter brain
- only effective if used with Levodopa
ADR of COMT (6)
- Increase abnormal movements (dyskinesia)
- Liver dysfunction (Tolcapone)
- Urine discoloration
- N/V, diarrhoea
- Visual hallucinations
- Daytime drowsiness & sleep disturbances
Examples of COMT (2)
- Entacapone
2. Tolcapone
Dopamine agonists MOA
- bind to dopamine receptors in brain to reduce symptoms of PD
- anti-PD effect not superior to levodopa
- prevent / delay onset of motor complications
ADR of Dopamine agonists (6)
- Similar to Levodopa
- “ergot” derivative - fibrosis
- arrythmias
- somnolence (pramipexole & ropinirole)
- pedal edema
- restrictive valvular heart disease (pergolide)
Examples of Dopamine agonists (5)
- Bromocriptine
- Pergolide (RVHD)
- Pramipexole (somnolence)
- Piribedil
- Ropinirole (somnolence)
Dopamine agonists for PD
- Symptomatic monotherapy
- Adjunctive therapy to Levodopa
For younger patients, dopamine agonists > levodopa as first line
Amantadine MOA
- Dopamine receptor agonists
- Release stored dopamine into synapse
- Inhibit pre-synaptic reuptake of catecholamines
- NMDA receptor antagonists
ADR of Amantadine (6)
- Psychological (anxiety, suicidal ideations, insomnia, schizophrenia)
- Seizures
- SJS
- Livedo reticularis (venule swelling due to thromboses)
- Cognitive impairment
- Hallucinations & nightmares
Benefit of Amantadine
- anti-dyskinetic (used for patients w motor fluctuations)
Initial clinical indications of Amantadine
anti-viral
Advantage of MAO-B inhibitor (Selegiline)
- may delay the degeneration of nigral brain cells
Advantage of COM-T inhibitors (Entacapone & Tolcapone)
- Increase the duration of action of each dose of levodopa
- Beneficial for “wearing off” responses
Advantage of Dopamine Agonists
Delay or prevent the onset of motor complications
Livedo reticularis
- venule swelling due to thromboses
- mottled reticulated discolouration of limbs
Drugs and their advantages (4)
- MAO-B inhibitors
- delay the degeneration of nigral brain cells - COM-T inhibitors
- extend the duration of action of levodopa for each doses by inhibiting the conversion to inactive form - Dopamine agonists
- delay the onset of motor complications (anti-dyskinetic) - Amantadine
- anti-dyskinetic (used for patients w motor fluctuations)
Mild antiparkinson activity
- MAO-B inhibitors
2. Amantadine
Any significance prevalence rates of PD between races
No
Average onset of PD
early-mid 60s
Anti-dyskinetic vs Delay/Prevent onset of motor fluctuations
Anti-dyskinetic
- reduce motor fluctuations
- used if patients have motor fluctuations
- amantadine
Delay/Prevent onset of motor fluctuations
- used before patients have motor fluctuations
- dopamine agonists
